The absence of the Autoimmune regulator (Aire) protein causes inflammation of multiple organs, in human patients with autoimmune polyglandular syndrome (APS I) and in mice with deficiencies of the aire gene. Inflammation is accompanied by autoantibodies to organ-specific antigens. In aire-/- mice, lymphocytes are required for development of chronic inflammation, and a majority of lymphocytes in inflammatory lesions are B cells. The goal of this study is to test the hypothesis that the activation of self-reactive B lymphocytes makes an important contribution to the autoimmune attack against organ-specific antigens. The specific aims of this study include: 1) assessing whether B cells are required for the development of organ-specific autoimmune disease, determining the ability of self-reactive immunoglobulin to elicit or accelerate disease, and establishing which effector molecules are essential for the emergence of inflammatory B cells, and 2) identifying a panel of tissue-specific antigens recognized by self-reactive aire-/- B and T cells. Because Aire function is critical to the thymic expression of peripheral organ-specific proteins and to clonal deletion of self-reactive thymocytes, establishing a coincidence between thymically expressed antigens and the specificities of disease-associated lymphocytes will be crucial in understanding how central tolerance prevents organ-specific pathology. Defining the lymphocyte subsets and the effector molecules that operate in the progression of autoimmune disease may suggest novel, directed therapeutic strategies.